The long-term goal of this research project will continue to be investigated and determine the specific factors that lead to development of endometrial cancer in postmenopausal women. Initial studies indicate that the postmenopausal women with endometrial cancer have hyperinsulinemia and insulin resistance. Insulin along with LH stimulates production of aromatizable androgens by the ovarian stroma of postmenopausal women with endometrial cancer resulting in increased prehormone availability for estrogen formation from perpheral conversion. Since endometrium has specific binding sites for insulin, we hypothesize that insulin might have an effect on the endometrium as well and play a role in the growth and development of the endometrial cancer. FIRST AIM of this continuing research project will be to fully characterize the nature of insulin resistance in women with endometrial cancer. In addition to 125I insulin binding studies in circulating monocytes, euglycemic insulin clamp techniques will be used to assess glucose utilization in vivo. The results of the in vivo studies will be compared with the detailed in vitro analysis of the insulin receptor autophosphorylation and insulin stimulated tyrosine kinase activity in freshly isolated moncytes and in cultured skin fibroblasts. SECOND AIM will be to perform studies on the ovarian stroma of postmenopausal women with endometrial cancer to investigate the mechanbism by which insulin stimulates ovarian steriodogenesis. Insulin could increase the responsiveness of the ovary to LH by increasing the number of LH receptors. The effect of insulin on LH binding in the ovarian stroma will be investigated. THIRD AIM will be to investigate the possible role of insulin on the development and progression of endometrial cancer. Functionality of the insulin receptors in the endometrial cancer tissue will be assessed by insulin receptor tyrosine kinase activity. The growth promoting activity of insulin on human endometrial cancer cells in long-term culture will be investigated. FOURTH AIM will be to investigate the role of estradiol, progesterone and various growth factors (IGF-I, IGF-II, epidermal growth factor and TGFa) in the growth and development of endometrial cancer. The proliferative effect of estrogen could be mediated through one or more of these growth factors. The interaction of estrogen and progesterone and the growth factors will be investigated on endometrial cancer cells in culture. Effect of the sex steriods on the secretion of IGFs and induction of the receptors for growth factors will be studied. The mitogenic effect and the receptor binding of various growth factors on human endometrial cancer cells in long term culture will be investigated. Since IGF-I action is locally modulated by IGF binding proteins, we will investigate the effect of insulin, IGF-I, estradiol and progesterone on the secretion of binding proteins by the cancer and will help development of preventive measures and therapeutic approaches to improve cure rate.